Efficacy of long-term milnacipran treatment in patients meeting different thresholds of clinically relevant pain relief: subgroup analysis of a randomized, double-blind, placebo-controlled withdrawal study

Abstract

Philip J Mease,1 Daniel J Clauw,2 Joel M Trugman,3 Robert H Palmer,3 Yong Wang3 1Swedish Medical Center and University of Washington, Seattle, WA, USA; 2Chronic Pain and Fatigue Research Center, University of Michigan Health System, Ann Arbor, MI, USA; 3Forest Research Institute, Jersey City, NJ, USA Background: Fibromyalgia patients from a long-term, open-label study of milnacipran (50–200 mg/day) were eligible to participate in a 12-week, randomized, placebo-controlled withdrawal study. The withdrawal study evaluated loss of therapeutic response in patients who achieved ≥50% pain improvements after receiving up to 3.25 years of milnacipran. This post-hoc analysis investigated whether patients who met lower thresholds of pain improvement also experienced worsening of fibromyalgia symptoms upon treatment withdrawal. Method: Among patients who received milnacipran ≥100 mg/day during the long-term study, three subgroups were identified based on percentage of pain reduction at randomization: ≥50% (protocol-defined "responders"; n=150); ≥30% to <50% (patients with clinically meaningful pain improvement; n=61); and <30% (n=110). Efficacy assessments included the visual analog scale (VAS) for pain, Fibromyalgia Impact Questionnaire-Revised (FIQR), 36-Item Short-Form Health Survey Physical Component Summary (SF-36 PCS), and Beck Depression Inventory (BDI). Results: In the ≥30 to <50% subgroup, significant worsening in pain was detected after treatment withdrawal. The difference between placebo and milnacipran in mean VAS score changes for this subgroup (+9.0, P<0.05) was similar to the difference in protocol-defined responders (+9.4, P<0.05). In the <30% subgroup, no worsening in pain was observed in either treatment arm. However, patients in this subgroup experienced significant worsening in FIQR scores after treatment withdrawal (placebo, +6.9; milnacipran, -2.8; P<0.001), as well as worsening in SF-36 PCS and BDI scores. Conclusion: Patients who experienced ≥30% to <50% pain reduction with long-term milnacipran had significant worsening of fibromyalgia symptoms after treatment withdrawal. These results suggest that the conventional ≥30% pain responder cutoff may be adequate to demonstrate efficacy in randomized withdrawal studies of fibromyalgia. Patients in the <30% pain reduction subgroup had worsening scores on the FIQR and other multidimensional measures after treatment withdrawal, indicating the importance of identifying and managing the multiple symptoms of fibromyalgia. Keywords: fibromyalgia, responders, post-hoc analysis, symptoms